Since monoclonal antibodies (mAb) specific for CD4 are potent inhibitors of HIV and SIV replication in vitro, we explored their potential usefulness in vivo as an AIDS therapy. the anti-CD4 mAb 5A8 efficiently inhibits HIV and SIVmac replication in vitro and virus-induced cell fusion. This antibody binds to domain 2 of the CD4 molecule and inhibits virus replication at a post-virus binding step. A single 3 mg/kg intravenous administration of mAb 5A8 in normal rhesus monkeys coated all circulating and lymph node CD4 cells for 4-6 days. CD4 cells were not cleared from circulation, but rather increased in number. These animals retained normal in vitro lymphocyte proliferative responses and generated normal humoral responses. The loss of cell coating with mAb 6-10 days following mAb administration coincided with the appearance of anti-mouse lg antibodies. Monkeys chronically infected with SIVmac that received a mAb of irrelevant specificity for 9-25 days all showed a transient increase in SIVmac provirus in PBL as measured by a quantitative polymerase chain reaction technique. In contrast, infected monkeys with >800 CD4 cells/ul treated with <800 CD4 cells/ul had marginal anti-mouse lg responses and could be treated with anti-CD4 mAb for 12-25 days. The three 5A8-treated monkeys with <800 CD4 cell/ul all exhibited 5-10 fold decreases in SIVmac provirus load over the treatment period. Thus, the passive administration of anti-CD4 mAb may exert a specific anti-viral effect in the AIDS virus-infected individual.